RORα (also known as NR1F1, RORA or RZR) is a member of the steroid hormone receptor superfamily, and is a transcriptional factor that regulates gene expression. RORα consists of an N-terminal transactivation domain, a DNA-binding domain, and a C-terminal ligand-binding domain. RORα binds to ROR-binding response elements (ROREs) in the promoter of target genes, and RORE contains hexanucleotide motifs (5-AGGTCA-3′) and A/T rich sequences of 6 base pairs preceding the hexanucleotide (Jetten A M et al., (2001) Prog Nucleic Acid Res Mol Biol. 69:205-47). The activity of RORα is regulated by the binding of a ligand to the C-terminal ligand-binding domain, and known ligands include cholesterol, cholesterol derivatives, melatonin, and CGP52608, which is one of thiazolidinediones (Kallen J et al., (2002) Structure. 10:1697-707/Kallen J et al., (2004) J Biol Chem. 279:14033-8/Wiesenberg I et al., (1995) Nucleic Acids Res. 23:327-33). It has been discovered by X-ray crystallography that cholesterol and cholesterol derivatives bind to the ligand-binding domain of RORα (Kallen J A et al., (2002) Structure. 10:1697-707/Kallen J et al., (2004) J Biol Chem. 279:14033-8). It has also been reported that melatonin specifically binds to RORα to induce RORα-mediated gene activity regulation, and that CGP52608 is a synthetic ligand that binds to RORα competitively with melatonin (Wiesenberg I et al., (1995) Nucleic Acids Res. 23:327-33). RORα regulates genes expressing Apo A, Apo V, and Apo C III, which are apolipoproteins, thereby transferring cholesterol of the peripheral tissue to the liver for removal (Vu-Dac N et al., (1997) J Biol Chem. 272:22401-4/Lind U et al., (2005) Biochem Biophys Res Commun. 330:233-41). This suggests that RORα may be applicable to the regulation of homeostasis of cholesterol and lipid metabolism-related diseases.

Liver X receptor α (LXRα) is a transcriptional factor whose activity is regulated by ligands, and is a member of the nuclear hormone receptor superfamily (Baranowski M. (2008) J Physiol Pharmacol. Suppl 7:31-55). LXRα is a vital factor in lipid and carbohydrate metabolism, and increases the expression of SREBP-1, FAS and SCD-1 genes to induce fatty acid biosynthesis in the liver (Joseph S B et al., (2002) J Biol Chem. 277:11019-25). Due to an increase in LXRα-mediated expression of these genes, the accumulation of triglycerides occurs in hepatocytes, and this causes fatty liver and hypertriglyceridemia. In other words, the expression of enzymes that induce lipid synthesis in the liver is increased by LXR activators, and this causes hyperlipoidemia and fatty acid (Schultz J R et al., (2000) Genes Dev. 14:2831-8). Among these enzymes, fatty acid synthase (FAS) is an enzyme that participates in the final stage of fatty acid biosynthesis, and is also a target gene of LXR and SREBP-1 (Clarke S D. (1993) J Anim Sci. 71:1957-65). It is known that RORα contributes to regulating genes that are vital for lipid synthesis, by crosstalk with LXR (Wada T et al., (2008) Exp Biol Med (Maywood)).
Acetyl-CoA carboxylase (ACC) is a major enzyme in the fatty acid production pathway that regulates the conversion of acetyl-CoA into malonyl-CoA (Tong L et al., (2006) J Cell Biochem. 99:1476-88). Malonyl-CoA produced by ACC inhibits CPT-1, which is an enzyme that plays a key role in inducing fatty acid oxidation in mitochondria, thereby inhibiting the oxidation of fatty acids, and ACC is inactivated and loses the ability to inhibit the oxidation of fatty acids when serine residues thereof are phosphorylated by a kinase such as AMPK (Brownsey R W et al., (2006) Biochem Soc Trans. 34:223-7).